The present invention relates to piperidine derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and their use in therapy.
The P2X7 receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in the inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X7 receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of interleukin-1xcex2 (IL-1xcex2) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and L-selectin shedding (lymphocytes). P2X7 receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells) and hepatocytes.
It would be desirable to make compounds effective as P2X7 receptor antagonists for use in the treatment of inflammatory, immune or cardiovascular diseases, in the aetiologies of which the P2X7 receptor may play a role.
In accordance with the present invention, there is therefore provided a compound of formula (I): 
where
A is phenyl or a 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from O, N or S; and optionally substituted by C1-6alkyl, halogen, nitro, amino, alkylamino, CF3, SO2Me, NHSO2Me or cyano;
B is Cxe2x95x90O, NH or SO2;
X is Cxe2x95x90O, CH(Me), O or (CH2)p where p is 0 or 1;
Y is O, CH2, NH or S;
Z is Cxe2x95x90O or SO2, provided that when Z is Cxe2x95x90O, then Y is O, CH2 or S;
R is hydrogen or C1-6alkyl;
R1 is hydrogen, halogen;
R2 is phenyl optionally substituted by CO2H, CO2alkyl, CONH2 or R2 is OH, NHR3, NHCH(R4)(CHR5)nR6, NHxe2x80x94R7xe2x80x94R8, SO2NHalkyl, NHCOalkyl, NHSO2alkyl, morpholine, NR9R10, piperazine substituted by phenyl, alkoxyphenyl, pyridyl or fluorophenyl;
n is 0, 1 or 2;
R3 is hydrogen, a bi- or tricyclic saturated ring system optionally containing a nitrogen atom, piperidinyl, alkylpyrollidine, ethynylcyclohexyl, a 5-membered aromatic ring containing 2 or 3 heteroatoms, C4-6 cycloalkyl optionally substituted by alkyl, cyano or hydroxy, or C1-8alkyl optionally containing an oxygen atom in the alkyl chain and being optionally substituted by one or more substituents selected from ethynyl, cyano, fluoro, di-alkylamino, hydroxy, thioalkyl, CO2R11 or CONH2;
R4 is hydrogen or alkyl optionally substituted by hydroxy or alkoxy;
R5 is hydrogen or hydroxy;
R6 is CO2R11, NHCO2R12, CONH2 or a 5 or 6-membered saturated ring containing an oxygen atom, a 5-membered heterocyclic ring containing one or two heteroatoms selected from O, N or S, or phenyl optionally substituted by one or more groups selected from alkyl, hydroxy, amino, alkoxy, or nitro;
R6 is alkyl;
R7 is a cyclopentane ring;
R8 is phenyl;
R9and R10 are independently hydrogen, benzyl, alkenyl, cycloalkyl, alkyl optionally substituted by hydroxy, alkoxy, cyano, dialkylamino, phenyl, pyridyl or CO2R11 or R9 and R10 together form a 5- to 7-membered saturated or partially saturated ring optionally containing a further heteroaton and optionally substituted by one or more groups selected from alkyl (optionally containing an oxygen atom in the chain and optionally substituted by hydroxy), COalkyl, CO2R11, COR13R14, CHO or piperidine,
R11 is hydrogen or alkyl;
R12 is alkyl; and
R13 and R14 are independently hydrogen or alkyl, and pharmaceutically acceptable salts and solvates thereof
In the context of the present specification, unless otherwise indicated, an alkyl substituent or alkyl moiety in a substituent group may be linear or branched and may contain up to 6 carbon atoms, examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl and n-hexyl.
Suitably A is phenyl or a 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from O, N or S; and optionally substituted by C1-6alkyl, halogen, nitro, amino, alkylamino, CF3, SO2Me, NHSO2Me or cyano. Examples of suitable 5- or 6-membered heterocyclic rings include. Preferably A is optionally substituted phenyl, more preferably A is phenyl substituted by a nitro group.
Suitably B is Cxe2x95x90O, NH or SO2. Preferably B is Cxe2x95x90O.
Suitably X is Cxe2x95x90O, CH(Me), O or (CH2)p where p is 0 or 1, Y is O, CH2, NH or S and Z is Cxe2x95x90O or SO2. Examples of groups formed by X, Y and Z include benzoxazinone and dihydroquinoline. Preferably X is CH2, Y is O and Z is Cxe2x95x90O such that X, Y and Z together form part of a benzoxazinone ring which can be optionally substituted by methyl.
Suitably R is hydrogen or C1-6alkyl, preferably R is hydrogen.
Suitably R1 is hydrogen or halogen, preferably R1 is hydrogen.
Suitably R2 is phenyl optionally substituted by CO2H, CO2alkyl, CONH2 or R2 is OH, NHR3, NHCH(R4)(CHR5)nR6, NHxe2x80x94R7xe2x80x94R8, SO2NHalkyl, NHCOalkyl, NHSO2alkyl, morpholine, NR9R10, piperazine substituted by phenyl, alkoxyphenyl, pyridyl or fluorophenyl. Preferably R2is NR9R10 where one of R9 or R10 is hydrogen and the other is alkyl such as CH(CH3)2.
Particularly preferred compounds of the invention include those exemplified herein both in free base form as well as all pharmaceutically acceptable salts and/or solvates thereof
According to the invention there is further provided a process for the preparation of a compound of formula (I) which comprises reaction of a compound of formula (II): 
where R, R1, X, Y and Z are as defined in formula (I) or a protected derivative thereof, with a compound of formula (III): 
where B and R2 are as defined in formula (I) or a protected derivative thereof, and L is a leaving group, and optionally thereafter in any order:
converting one or more functional groups into further functional groups
removing any protecting groups
forming a pharmaceutically acceptable salt or solvate.
Examples of suitable leaving groups L include halogen, OMs and OTs. Preferably L is halogen, in particular chloro.
The reaction of compounds of formula (II) and (III) is preferably carried out in the presence of an organic amine such as a trialkylamine, for example triethylamine. The reaction is preferably carried out in an inert solvent such as NMP, DMF or dioxan preferably at elevated temperature, for example at the reflux temperature of the reaction mixture.
Compounds of formulae (II) can be prepared as follows:
(a) by reacting a compound of formula (IV): 
xe2x80x83in which X, Y and Z are as defined in formula (II) or are protected derivatives thereof, with a compound of formula (V): 
xe2x80x83in which R20 is a leaving group or an activated hydroxy group, or
(b) by reacting a compound of formula (VI): 
xe2x80x83in which P a protecting group, with a compound of formula (VII): 
xe2x80x83in which the groups L are leaving groups.
Compounds of formulae (IV) and (V) can be reacted under Mitsonobu conditions when R20 in compound (V) is an activated hydroxy group. For the reaction of compounds (VI) and (VII), examples of suitable leaving L groups include halogen, in particular chloro, or imidazole. Alternatively triphosgene can be used. Suitable protecting groups for compounds (V) and (VI) include t-butoxy carbonyl (Boc).
Compounds of formula (III), (IV), (V) and (VII) are prepared using Iterature procedures or are commercially available.
Functional groups can be converted into further functional groups using procedures known in the art. For example a carboxylic acid group can be converted into an ester or amide using standard chemistry.
Protecting groups can be added and removed using known reaction conditions. The use of protecting groups is fully described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J W F McOmie, Plenum Press (1973), and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 2nd edition, T W Greene and P G M Wutz, Wiley-Interscience (1991).
Deprotection can be carried out using methods generally known in the art.
All novel intermediates form a further aspect of the invention.
The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate, or an alkali metal salt such as a sodium or potassium salt.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
The compounds of the present invention are advantageous in that they possess pharmacological activity and have utility as modulators of P2X7 receptor activity. They are therefore indicated as pharmaceuticals for use in the treatment or prevention of rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, hyperresponsiveness of the airway, chronic obstructive pulmonary disease (COPD), bronchitis, septic shock, glomerulonephritis, irritable bowel disease, Crohn""s disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, neurodegenerative disease, Alzheimer""s disease, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke, peripheral vascular disease and varicose veins.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
The invention further provides a method of effecting immunosuppression (e.g. in the treatment of rheumatoid arthritis, irritable bowel disease, atherosclerosis or psoriasis) which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined to a patient.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.10 to 70% w, of active ingredient, and, from 1 to 99.95% w, more preferably from 30 to 99.90% w, of a pharmaceutically acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.
The present invention will now be further illustrated by reference to the following examples.